Abstract: African American (AA) women are more likely receive an inconclusive genetics test diminishing the utility and impact of genetics and precision medicine technologies on cancer management and prevention. In fact, actionable mutations are found less frequently in women of African descent. ?Actionable? mutations are mutations whose phenotype would result in specific, defined medical recommendation(s) and allow the proper deployment of risk reduction strategies such as early detection, prophylactic surgery, chemoprevention, and lifestyle modifications. Additionally, with the high prevalence of variants of unknown significance (VUSs) in the population, additional research is warranted to determine the functional consequences of VUSs. Through this R15 mechanism, we seek to expand our previous research which identified 29 BRCA VUSs in 30 high-risk families thought to have meaningful clinical significance in treatment strategies. Using CRISPR methods will allow us to determine the functional significance of novel variants comparing wild-type parental cell lines to genetically edited, derived cell lines. The functionalization of VUSs using CRISPR will allow for improved risk prediction, improved tumor targeting and thus, improved outcomes in a population not well represented in genomic studies and disproportionately affected by VUSs. Our overall hypothesis is that African American breast cancer patients have a unique genetic profile not currently represented in commercially available genetic tests that could be readily discovered in our distinctive family-case-control study. We also hypothesize that VUSs in actionable genes, especially those that hypothetically alter the function of the gene leading to changes in tumor cell behavior, could be characterized using novel tools such as CRISPR. We plan to test our hypothesis and accomplish the overall goals of this application by pursuing the following specific aims: 1) to prioritize, characterize, and validate novel and genetic variants of unknown significance and determine their association with BCA risk in AAs; 2) to use CRISPR-Cas9 editing to determine the functional consequences of VUSs in actionable DNA-repair pathways overrepresented in African American breast cancer cases. The lack of research in under-represented health disparity populations, such as AAs, hampers efforts to reduce and eliminate BCa disparities. This proposal will allow us to better understand the genotypic indicators that may confer risk for developing BCa and allow us to generate knowledge related to the biological indicators of the disease. This grant mechanism will also help promote the development of burgeroning nurse scientists within an interdisciplinary team of scientists committed to the development of precision medicine strategies to reduce BCa disease burden in African Americans.